CN106365986B - Compound and preparation method thereof and the purposes in synthesis Bu Waxitan - Google Patents
Compound and preparation method thereof and the purposes in synthesis Bu Waxitan Download PDFInfo
- Publication number
- CN106365986B CN106365986B CN201510430387.9A CN201510430387A CN106365986B CN 106365986 B CN106365986 B CN 106365986B CN 201510430387 A CN201510430387 A CN 201510430387A CN 106365986 B CN106365986 B CN 106365986B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- preparation
- chloride
- waxitan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/38—Acyl halides
- C07C53/46—Acyl halides containing halogen outside the carbonyl halide group
- C07C53/50—Acyl halides containing halogen outside the carbonyl halide group of acids containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/32—Oxygen atoms
- C07D307/33—Oxygen atoms in position 2, the oxygen atom being in its keto or unsubstituted enol form
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application provides a kind of Formula II and IV compound.The application also provides Formula II compound for synthesizing the purposes and synthetic method of Bu Waxitan.The raw material that herein described method is related to is easy to get and cheap, can prepare the Bu Waxitan of high-optical-purity.
Description
Technical field
This application involves pharmaceutical synthesis fields, and in particular, to compound and preparation method thereof is with it in synthesis Bu Waxi
Purposes in smooth.The application further relates to a kind of method for synthesizing Bu Waxitan.
Background technique
Epilepsy is the common disease of nervous system, and the disease incidence in crowd is 0.6%~1.1%, wherein 60%~70%
Patient can still break out when taking anti-epilepsy agent, cause a part of patient voluntarily to stop drug therapy.China has about 600 at present
Ten thousand or more epileptic, annual new hair epileptic 650,000~700,000, about 25% is intractable epilepsy.Although current epilepsy
Diagnosis and treatment make great progress, but the quantity for the treatment of of intractable epilepsy is increasing.Broad sense intractable epilepsy refers to
Using current antiepileptic (AEDs) Canonical management, cannot terminate its breaking-out or by clinical confirmation be refractory epilepsy and
Epilepsy syndromes.
Bu Waxitan (Brivaracetam) is the synaptic vesicle proteins 2A ligand of a novel high-affinity, be can inhibit
Neuronal voltagedependent sodium channel, for treating intractable epilepsy partial seizures.The II phase of Bu Waxitan, III phase are clinical
Test all has a better effect.The incidence of the main adverse events of Bu Waxitan is similar to the incidence of placebo, is
Slightly to the fatigue of moderate, headache, nasopharyngitis, nausea, drowsiness and dizzy.No patient interrupts treatment because of adverse events.As a result
Show Bu Waxitan piece to be in 16~65 years old intractable epilepsy partial seizures patient be the adjuvant treatment age it is effective and
Tolerance is good.In general, it is insane to be that the very good third generation of a prospect after Levetiracetam resists by Bu Waxitan
Epilepsy class drug.
So far, the domestic patent about Bu Waxitan synthesis has not been reported.External related patents report is also few,
Such as patent US 6,784,197, US 7,629,474, US 8,957,226, US 8,338,621, US 8,076,493 and its
Related patents report the synthesis of Bu Waxitan, wherein 6 US, and 784,197, US 7,629,474 report some synthetic routes,
The problems of these synthetic routes are concentrated mainly on, can not in high yield, highly selective synthesizing optical purity it is enough
There is the operation side for needing column chromatographic purifying, chiral high performance liquid chromatography purifying etc. to be unfavorable for industry's enlarging production in Bu Waxitan
Method.
Accordingly, there exist to it is simple and low in cost, without chiral resolution, be easy to industry amplification the side for preparing Bu Waxitan
The demand of method, to obtain the Bu Waxitan of high-purity, high optical activity.
Summary of the invention
The purpose of the application is to provide a kind of Formula II compound and preparation method thereof.
The further object of the application is to provide Formula II compound for synthesizing with the purposes of Formula V Bu Waxitan.
The other purpose of the application is to provide a kind of formula IV compound and preparation method thereof.
A further object of the application is to provide a kind of method for synthesizing Formula V Bu Waxitan.
On the one hand, the application provides a kind of compound, and the compound has the structure of Formula II:
On the other hand, the application provides a kind of method for being used to prepare Formula II compound, and the method includes passing through Formulas I
The step of closing object preparation formula II compound:
It will be appreciated by those skilled in the art that can be by open-loop method known in the art by compound of formula I system
Standby Formula II compound, such as by making compound of formula I in ZnCl2Under the action of react to obtain Formula II compound with thionyl chloride.
In above or other embodiments, can 0 DEG C to reflux at a temperature of, it is preferable that between 55 DEG C -80 DEG C
At a temperature of, in ZnCl2Under the action of, react thionyl chloride with compound of formula I；Preferably, thionyl chloride is simultaneously as anti-
The use molar equivalent of the solvent and thionyl chloride answered is between 1-50, it is highly preferred that the use mole of the thionyl chloride is worked as
Amount is between 2-5.
In some embodiments, following preparation of compounds of formula I can be passed through:
Wherein, R C1-20Alkyl, it is preferable that R is methyl, ethyl, propyl, allyl, normal-butyl, isobutyl group, isopropyl
Base, n-pentyl, n-hexyl, tert-butyl or benzyl, more preferably R are ethyl.
In above or other embodiments, Formula IV compound can be commercial products, such as super happy chemical article No. SP-
13711 product.
In above or other embodiments, Formula IV compound can also be prepared in the following manner:
Wherein reaction temperature is 0 DEG C -100 DEG C, and alkali uses molar equivalent between 1 and 3, and the use mole of compound 2 is worked as
Amount is between 1 and 3；Preferably, the alkali is selected from one of metallic sodium, metallic potassium or more, it is highly preferred that the metal
Sodium is sodium methoxide, sodium ethoxide or sodium tert-butoxide, and the metallic potassium is potassium tert-butoxide；The organic solvent 4 be selected from ethyl alcohol, methanol,
One of propyl alcohol, isopropanol or more.
In above or other embodiments, in which:
By Formula IV preparation of compounds of formula VII compound:
- 78 DEG C to 200 DEG C at a temperature of, in aprotic organic solvent, make Formula IV compound and ethyl metal reagent
Preparation formula VII compound is reacted, wherein the use molar equivalent of ethyl metal reagent is between 1-5；Preferably, the ethyl gold
Belong to reagent and is selected from one of ethylmagnesium bromide, ethylmagnesium chloride, diethyl zinc, ethyl-lithium and lead diethide or more；More
Preferably, the ethyl metal reagent is used in combination with cuprous iodide, cuprous cyanide or anhydrous zinc chloride, and iodate is sub- in reaction
The use molar equivalent of copper, cuprous cyanide or anhydrous zinc chloride is between 0.01-2；Preferably, the aprotic organic solvent choosing
From one of tetrahydrofuran (THF), methyltetrahydrofuran, toluene, methylene chloride, ether and methyl tertiary butyl ether(MTBE) or more
Kind；
By Formula VII preparation of compounds of formula Compound I:
In the mixture of water-soluble high boiling organic solvent and water, under the action of salt or alkali, at 50 DEG C -200 DEG C
Within the temperature range of make the experience takes off ester group reaction of Formula VII compound to obtain compound of formula I, wherein the use mole of salt or alkali is worked as
Amount is between 0.01-10；Preferably, the salt is selected from one of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and lithium bromide
Or more, the alkali is selected from one of lithium hydroxide, potassium hydroxide or sodium hydroxide or more, the water-soluble height
Boiling point organic solvent is selected from N-Methyl pyrrolidone, n,N-Dimethylformamide, dimethyl sulfoxide, sulfolane and 4- methyl -2-
One of amylalcohol or more；
Or, making Formula VII compound remove R group by metal catalytic first if R contains unsaturated part, then existing
Compound of formula I is obtained through decarboxylic reaction within the temperature range of 25 DEG C -200 DEG C；Preferably, the depickling reaction is selected from first
One of benzene, methyl tertiary butyl ether(MTBE), N-Methyl pyrrolidone, n,N-Dimethylformamide and dimethyl sulfoxide or it is a variety of in into
Capable.
It yet still another aspect, the application provides a kind of compound, the compound has the structure of formula IV:
It yet still another aspect, the application provides a kind of method for being used to prepare above-mentioned formula IV compound, the method includes logical
That crosses Formula II compound and (S) -2- amino butanamide or its salt reacts the compound for carrying out preparation formula IV:
It will be appreciated by those skilled in the art that can be by amide key-forming method known in the art by Formula II chemical combination
Object preparation formula IV compound.
It, can under alkaline condition, in organic solvent 1, at -20 DEG C -100 DEG C in above or other embodiments
At a temperature of, so that Formula II compound and (S) -2- amino butanamide or its reactant salt is carried out preparation formula IV compound, wherein being used to form
Between 1-5, the use molar equivalent of (S) -2- amino-butanamide or its salt exists the use molar equivalent of the alkali of alkaline condition
Between 0.5-5；Preferably, the alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, potassium hydroxide, carbonic acid
Sodium, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides or two (three
Methylsilyl) one of Sodamide or more, the organic solvent 1 be selected from tetrahydrofuran, methyltetrahydrofuran, ether,
Methylene chloride, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol, isopropanol, n,N-Dimethylformamide, N- methylpyrrole
One of alkanone, dimethyl sulfoxide or more.
In other respects, the application provides the method for preparation formula V Bu Waxitan a kind of, and the method includes making formula IV chemical combination
Object cyclization synthesizes Formula V Bu Waxitan:
It will be appreciated by those skilled in the art that can be by nucleophilic displacement process known in the art by formula IV chemical combination
Object preparation formula V compound Bu Waxitan.
It, can under alkaline condition, in organic solvent 2, at -78 DEG C -100 DEG C in above or other embodiments
At a temperature of, make formula IV that itself ring closure reaction preparation formula V Bu Waxitan occur, wherein the use for being used to form the alkali of alkaline condition rubs
That equivalent is between 1-5；Preferably, the alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, sodium hydroxide, hydroxide
Potassium, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (trimethyl silicon substrate) lithium amides
Or two one of (trimethyl silicon substrate) Sodamides or more, organic solvent 2 is selected from tetrahydrofuran, methyltetrahydrofuran, second
Ether, methylene chloride, chloroform, acetonitrile, Isosorbide-5-Nitrae-dioxane, methanol, ethyl alcohol, isopropanol, n,N-Dimethylformamide, N- methyl pyrrole
One of pyrrolidone, dimethyl sulfoxide or more.
In a specific exemplary embodiment, described method includes following steps:
Compared with prior art, the method that the application is used to synthesize Bu Waxitan has the benefit that this synthetic route is logical
It crosses using the chiral raw material being easy to get and prepares the Bu Waxitan of high-optical-purity, avoid column chromatographic purifying etc. and be unfavorable for industry and put
The means of purification of mass production, can obtain high-quality, high-optical-purity product (in four kinds of optical isomers, Bu Waxitan ratio
99.5%) example is greater than, split without using expensive Chiral HPLC method, avoid waste of the chiral resolution for raw material.
Prepare the gross production rate about 40% of Bu Waxitan by compound of formula I, be higher than existing disconnecting route, and have advanced optimize promotion can
Energy.
Specific embodiment
Presently filed embodiment is described below by embodiment, it will be appreciated by the person skilled in the art that these
Specific embodiment only indicates to achieve the purpose that the application and the implementation technical solution that selects, is not to technical solution
Limitation.According to teachings of the present application, be to the improvement of technical scheme in conjunction with the prior art it is obvious, belong to the application
The range of protection.
Implementation condition used in the examples can do further adjustment according to specific requirement, and the implementation condition being not specified is logical
It is often the condition in routine experiment.
Wherein, the chemical reagent used in the examples below is commercially available chemical reagent.
In an exemplary embodiment of the present invention embodiment, Bu Waxitan is synthesized using following route:
In said synthesis route, those skilled in the art can also make a change said synthesis route, such as basis
It needs to change specific reaction condition or the synthetic route of a certain step or a few steps is adjusted, these are without departing from of the invention
Substantive content change made is within the scope of protection of this application.
1 preparation formula II compound of embodiment
Anhydrous zinc chloride (2.5g, 18.3mmol), which is added, to be had in reaction flask in 20mL thionyl chloride, then by Formulas I chemical combination
Object (12.0g, 93.7mmol).Reaction flask is placed in 55 DEG C of oil baths and is reacted, to gas chromatographic detection (gas chromatographic detection) nothing
Starting material left stops reaction, and system is cooled to room temperature, and screws out thionyl chloride, then obtain the formula of yellowish liquid through vacuum distillation
II compound, yield 68%.The nuclear magnetic data of Formula II compound is as follows:1H NMR (400MHz, CDCl3): δ 3.67 (1H, dd),
3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H, m), 0.93 (3H,
t)。
The specific rotatory power of compound II are as follows: [α]23 D=+2.9 (C=10, CHCl3)
2 preparation formula II compound of embodiment
Anhydrous zinc chloride (40g, 0.29mol), which is added, to be had in reaction flask in 400mL thionyl chloride, then by Formulas I chemical combination
Object (188g, 1.47mol).Reaction flask is placed in 85 DEG C of oil baths and is reacted, to GC detection without starting material left, stops reaction, system
It is cooled to room temperature, screws out thionyl chloride, then obtain the Formula II compound of yellowish liquid, yield 63.5% through vacuum distillation.
The nuclear magnetic data of Formula II compound is as follows:1H NMR (400MHz, CDCl3):1H NMR (400MHz, CDCl3): δ
3.67 (1H, dd), 3.59 (1H, dd), 2.58 (1H, dd), 2.40 (1H, dd), 2.20-2.31 (1H, m), 1.25-1.53 (4H,
M), 0.93 (3H, t).
The specific rotatory power of compound II are as follows: [α]23 D=+2.9 (C=10, CHCl3)
3 preparation formula IV compound of embodiment
The dry dichloro of 40mL is added in formula III compound (1.67g, 12mol) (being coupled Science and Technology Ltd. purchased from Beijing)
In methane, be added triethylamine (2.43g, 24mmol), at room temperature stir 30 minutes after, be added dropwise Formula II compound (2.0g,
10.8mmol), it is added dropwise, is stirred at room temperature to TLC and detects without starting material left.30mL water, 4mL ethyl alcohol is added, extraction has separated
Machine phase is extracted twice with 40mL methylene chloride, merges organic phase, and anhydrous sodium sulfate is dry, and drying finishes, and is filtered, filtrate concentration
Obtain the crude product of formula IV compound, yield 96.7%.
The nuclear-magnetism of formula IV compound after purification is obtained using column chromatographic purifying (solvent polarity: ethyl acetate 100%)
Data are as follows:1H NMR (400MHz, CDCl3) δ 6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, dd), 3.61
(2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97
(3H, t), 0.91 (3H, t).
The specific rotatory power of compound IV are as follows: [α]25 D=-23.7 (C=3, CH3OH)
4 preparation formula V compound of embodiment
By the crude product 10.0g (in terms of 40mmol) of formula IV compound made from method as described in Example 3, drying is added
In THF 150mL, potassium tert-butoxide (5.6g, 50mmol) is added in reaction flask.System is detected in -30 DEG C of reactions to TLC without original
Material is remaining, saturated ammonium chloride quenching reaction, separates organic phase, and water phase 50mL ethyl acetate extracts three times, merges organic phase, satisfy
It washed once with NaCl solution, anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give crude product, isopropyl ether mashing, and obtained solid is
Bu Waxitan, yield 93% can obtain high-purity product, the product of chiral HPLC > 99.5% through further recrystallization purifying.
The nuclear magnetic data of Formula V compound is as follows:1H NMR (400MHz, CDCl3) δ 6.45 (brs, 1H), 5.80 (brs,
1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd,
1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
5 preparation formula V compound of embodiment
By the crude product 10.0g (in terms of 40mmol) of formula IV compound made from method as described in Example 3, it is added dry two
In chloromethanes 150mL, by tetrabutylammonium chloride (2.3g, 10mmol), reaction flask is added in anhydrous sodium sulfate (5.6g, 40mmol)
In.Solid KOH (4.2g, 75mmol) system is added to detect in -10 DEG C of reactions to TLC without starting material left, saturated ammonium chloride is quenched
Reaction separates organic phase, and water phase 50mL methylene chloride extracts three times, merges organic phase, and saturation NaCl solution washed once, nothing
Aqueous sodium persulfate dries, filters, and filtrate is concentrated to give crude product, isopropyl ether mashing, and obtained solid is Bu Waxitan, yield 96%, warp
Further recrystallization purifying can obtain high-purity product, the product of chiral HPLC > 99.5%.
The nuclear magnetic data of Formula V compound is as follows:1H NMR (400MHz, CDCl3) δ 6.45 (brs, 1H), 5.80 (brs,
1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd,
1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
6 preparation formula IV compound of embodiment
100mL dry THF is added in formula III compound (5.0g, 36mol) (being coupled Science and Technology Ltd. purchased from Beijing)
In, be added triethylamine (7.3g, 72mmol), at room temperature stir 30 minutes after, be added dropwise Formula II compound (6.0g,
32.5mmol), it is added dropwise, is stirred at room temperature to TLC and detects without starting material left.100mL water is added, separates organic phase, uses 50mL
Ethyl acetate extracts three times, merges organic phase, and anhydrous sodium sulfate is dry, and drying finishes, and filters, and filtrate is concentrated to get formula IV chemical combination
The crude product of object.
The nuclear-magnetism of formula IV compound after purification is obtained using column chromatographic purifying (solvent polarity: ethyl acetate 100%)
Data are as follows:1H NMR (400MHz, CDCl3) δ 6.20-6.45 (2H, m), 5.69 (1H, brs), 4.46 (1H, dd), 3.61
(2H, d), 2.23-2.42 (3H, m), 1.85-1.97 (1H, m), 1.62-1.75 (1H, m), 1.23-1.53 (4H, m), 0.97
(3H, t), 0.91 (3H, t).
The specific rotatory power of compound IV are as follows: [α]25 D=-23.7 (C=3, CH3OH)
7 preparation formula V compound of embodiment
By the crude product (in terms of 36mmol) of formula IV compound made from method as described in Example 6, dry THF is added
In 100mL, potassium tert-butoxide (4.8g, 43.2mmol) is added in reaction flask.System is surplus without raw material to TLC detection in 0 DEG C of reaction
Remaining, saturated ammonium chloride quenching reaction separates organic phase, and water phase 50mL ethyl acetate extracts three times, merges organic phase, saturation
NaCl solution washed once, and anhydrous sodium sulfate dries, filters, and filtrate is concentrated to give crude product, isopropyl ether mashing, and obtained solid uses second
Isopropyl propionate recrystallizes to obtain Formula V compound as white solid, i.e. Bu Waxitan, chiral together with 2 liang of step total recoverys 49% of embodiment
HPLC purity > 99.5%.
The nuclear magnetic data of Formula V compound is as follows:1H NMR (400MHz, CDCl3) δ 6.45 (brs, 1H), 5.80 (brs,
1H), 4.47 (dd, 1H), 3.49 (dd, 1H), 3.06 (dd, 1H), 2.56 (dd, 1H), 2.25-2.40 (m, 1H), 2.05 (dd,
1H), 1.78-1.99 (m, 1H), 1.54-1.75 (m, 1H), 1.25-1.48 (m, 4H), 0.80-0.95 (m, 6H).
8 preparation of compounds of formula I of embodiment
It is complete that dissolution in 80mL dehydrated alcohol is added in sodium methoxide (2.05g, 38mmol).Reaction flask is placed in ice-water bath
In, diethyl malonate is added.It stirs 10 minutes at this temperature, system is warmed to room temperature, and is slowly added into reaction system
(R)-epoxychloropropane (ee 98%) (2.7mL, 35mmol) (purchased from resistance to Jilin Chemical is pacified), finishes, reacts under system counterflow condition
18 hours, stop reaction, system is cooled to room temperature, and is spin-dried for solvent, and 100mL water is added, and is extracted 3 times with 100mL ethyl acetate.It closes
And organic phase, anhydrous sodium sulfate is dry, and drying finishes, and filters, and filtrate is spin-dried for obtaining compound VI, is evaporated under reduced pressure to colourless liquid
Body, yield 55%.Compound VI chirality HPLC (ee 98%).
CuI (9.5g, 50mol) is added in 100mL dry THF, reaction flask is placed in -30 DEG C of low-temp reaction baths, to
The THF solution (1.0M, 300mL, 300mmol) that ethyl grignard reagent is added in reaction flask stirs 1 hour, then drips into reaction flask
Add the dry THF solution of the compound VI (20g, 117mmol) as made from the above method.It is added dropwise, stirs at this temperature
After 30 minutes, it is to slowly warm up to -15 DEG C.With saturated ammonium chloride quenching reaction, 1L water is added, three times with the extraction of 1L ethyl acetate,
Merge organic phase, anhydrous sodium sulfate is dry, and drying finishes, and filters, and filtrate is concentrated to get compound VII crude product.It is added into
LiCl (14.7g, 350mmol) is added in reaction flask DMSO/H2O (400mL/20mL).System 140 DEG C of reaction 18h it
Afterwards, it is poured into 400mL water, three times with the extraction of 400mL ethyl acetate, merges organic phase, saturation NaCl solution washed once, anhydrous
Sodium sulphate dries, filters, and filtrate is concentrated to give crude product, and vacuum distillation obtains compound I, colourless liquid, yield 50%.
The nuclear magnetic data of compound I is as follows:1H NMR (400MHz, CDCl3) δ 4.42 (1H, dd), 3.92 (1H, dd),
2.52-2.65 (2H, m), 2.18 (1H, dd), 1.40-1.47 (2H, m), 1.40-1.47 (2H, m), 1.27-1.39 (2H, m),
0.94 (3H, t).
The specific rotatory power of compound I are as follows: [α]23 D=+3.9 (C=10, CHCl3)
The application includes but is not limited to above embodiments, it is all carried out under the principle of the application spirit any equally replace
Generation or local improvement, all will be regarded as within the scope of protection of this application.
Claims (23)
1. a kind of compound, the compound has the structure of Formula II:
2. a kind of method for being used to prepare compound as described in claim 1, the method includes being prepared by compound of formula I
The step of Formula II compound:
3. according to the method described in claim 2, wherein 0 DEG C to reflux at a temperature of, in ZnCl2Under the action of, keep dichloro sub-
Sulfone is reacted with compound of formula I.
4. according to the method described in claim 3, wherein at a temperature of between 55 DEG C -80 DEG C, in ZnCl2Under the action of, make two
Chlorine sulfoxide is reacted with compound of formula I.
5. according to the method described in claim 3, the wherein thionyl chloride use as the solvent and thionyl chloride of reaction simultaneously
Molar equivalent is between 1-50.
6. according to the method described in claim 5, wherein the use molar equivalent of the thionyl chloride is between 2-5.
7. the method according to any one of claim 2-6, wherein pass through following preparation of compounds of formula I:
Wherein, R C1-20Alkyl.
8. according to the method described in claim 7, wherein R is methyl, ethyl, propyl, allyl, normal-butyl, isobutyl group, isopropyl
Base, n-pentyl, n-hexyl, tert-butyl or benzyl.
9. according to the method described in claim 7, wherein R is ethyl.
10. according to the method described in claim 7, wherein,
By Formula IV preparation of compounds of formula VII compound:
- 78 DEG C to 200 DEG C at a temperature of, in aprotic organic solvent, make Formula IV compound with optionally with cuprous iodide,
The ethyl metal reagent that cuprous cyanide or anhydrous zinc chloride are used in combination reacts preparation formula VII compound, and wherein ethyl metal tries
Agent uses molar equivalent between 1-5, and in the presence of cuprous iodide, cuprous cyanide or anhydrous zinc chloride, iodate in reaction
The use molar equivalent of cuprous, cuprous cyanide or anhydrous zinc chloride is between 0.01-2；
By Formula VII preparation of compounds of formula Compound I:
In the mixture of water-soluble high boiling organic solvent and water, under the action of salt or alkali, in 50 DEG C -200 DEG C of temperature
Make the experience takes off ester group reaction of Formula VII compound to obtain compound of formula I in degree range, wherein the use molar equivalent of salt or alkali exists
Between 0.01-10；
Or, if R contains unsaturated part, Formula VII compound is made to remove R group by metal catalytic first, then 25 DEG C-
Compound of formula I is obtained through decarboxylic reaction within the temperature range of 200 DEG C.
11. according to the method described in claim 10, wherein by Formula IV preparation of compounds of formula VII compound the step of in, institute
It states ethyl metal reagent and is selected from one of ethylmagnesium bromide, ethylmagnesium chloride, diethyl zinc, ethyl-lithium and lead diethide or more
It is a variety of；The aprotic organic solvent is selected from tetrahydrofuran (THF), methyltetrahydrofuran, toluene, methylene chloride, ether and first
One of base tertbutyl ether or more.
12. according to the method described in claim 10, wherein by Formula VII preparation of compounds of formula Compound I the step of in, it is described
Salt is selected from one of lithium chloride, sodium chloride, potassium chloride, magnesium chloride and lithium bromide or more, the alkali be selected from lithium hydroxide,
One of potassium hydroxide or sodium hydroxide or more, the water-soluble high boiling organic solvent are selected from N- crassitude
One of ketone, N,N-dimethylformamide, dimethyl sulfoxide, sulfolane and 4- methyl -2- amylalcohol or more.
13. according to the method described in claim 10, wherein the depickling reaction is selected from toluene, methyl tertiary butyl ether(MTBE), N-
One of methyl pyrrolidone, N,N-dimethylformamide and dimethyl sulfoxide or a variety of middle progress.
14. the purposes that compound as described in claim 1 is used to synthesize Formula V Bu Waxitan
15. a kind of compound, the compound has the structure of formula IV:
16. a kind of method for being used to prepare compound as claimed in claim 15, the method includes by such as claim 1
The compound and (S) -2- amino butanamide or its salt react the compound for carrying out preparation formula IV:
17. the method according to claim 11, wherein under alkaline condition, in organic solvent 1, at -20 DEG C -100 DEG C
At a temperature of, so that Formula II compound and (S) -2- amino butanamide or its reactant salt is carried out preparation formula IV compound, wherein being used for shape
At alkaline condition alkali using molar equivalent between 1-5, (S) -2- amino-butanamide or its salt are existed using molar equivalent
Between 0.5-5.
18. according to the method for claim 17, wherein the alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, hydrogen-oxygen
Change sodium, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (trimethyls
Silicon substrate) one of lithium amide or two (trimethyl silicon substrate) Sodamides or more, the organic solvent 1 be selected from tetrahydrofuran,
Methyltetrahydrofuran, ether, methylene chloride, chloroform, acetonitrile, 1,4- dioxane, methanol, ethyl alcohol, isopropanol, N, N- dimethyl
One of formamide, N-Methyl pyrrolidone, dimethyl sulfoxide or more.
19. a kind of method of preparation formula V Bu Waxitan, the method includes closing compound cyclization as claimed in claim 15
At Formula V Bu Waxitan:
20. according to the method for claim 19, wherein under alkaline condition, in organic solvent 2, at -78 DEG C -100 DEG C
At a temperature of, make formula IV that itself ring closure reaction preparation formula V Bu Waxitan occur, wherein being used to form the use of the alkali of alkaline condition
Molar equivalent is between 1-5.
21. according to the method for claim 20, wherein the alkali is selected from triethylamine, diisopropyl ethyl amine, pyridine, hydrogen
Sodium oxide molybdena, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamine, two (front threes
Base silicon substrate) one of lithium amide or two (trimethyl silicon substrate) Sodamides or more, organic solvent 2 is selected from tetrahydrofuran, first
Base tetrahydrofuran, ether, methylene chloride, chloroform, acetonitrile, 1,4- dioxane, methanol, ethyl alcohol, isopropanol, N, N- dimethyl methyl
One of amide, N-Methyl pyrrolidone, dimethyl sulfoxide or more.
22. a kind of method of preparation formula V Bu Waxitan, described method includes following steps:
The synthesis step of the Formula V Bu Waxitan includes by compound of formula I through ring-opening reaction preparation formula II compound；Formula II chemical combination
Object and (S) -2- amino butanamide or its reactant salt preparation formula IV compound；Formula IV compound synthesizes Formula V cloth watt through ring closure reaction
It is western smooth.
23. method as claimed in claim 22, wherein described method includes following steps:
Priority Applications (16)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510430387.9A CN106365986B (en) | 2015-07-21 | 2015-07-21 | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
| HUE16800643A HUE064612T2 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| HRP20240027TT HRP20240027T1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| US15/575,373 US10221134B2 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| KR1020177037062A KR102630456B1 (en) | 2015-05-25 | 2016-05-24 | Method of manufacturing brivaracetam |
| BR112017025266A BR112017025266A2 (en) | 2015-05-25 | 2016-05-24 | process to produce brivaracetam |
| PL16800643.5T PL3302441T3 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| EP16800643.5A EP3302441B1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| CA2984832A CA2984832A1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| JP2017561732A JP6872500B2 (en) | 2015-05-25 | 2016-05-24 | How to make bribalacetam |
| ES16800643T ES2965746T3 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| PCT/US2016/033965 WO2016191435A1 (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam |
| MX2017015133A MX2017015133A (en) | 2015-05-25 | 2016-05-24 | Processes to produce brivaracetam. |
| IL255880A IL255880B (en) | 2015-05-25 | 2017-11-23 | Processes to produce brivaracetam |
| US16/256,522 US20240199541A9 (en) | 2015-05-25 | 2019-01-24 | Processes to produce brivaracetam |
| US16/256,596 US11673862B2 (en) | 2015-05-25 | 2019-01-24 | Processes to produce brivaracetam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510430387.9A CN106365986B (en) | 2015-07-21 | 2015-07-21 | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106365986A CN106365986A (en) | 2017-02-01 |
| CN106365986B true CN106365986B (en) | 2019-01-08 |
Family
ID=57880081
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510430387.9A Active CN106365986B (en) | 2015-05-25 | 2015-07-21 | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106365986B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021260721A1 (en) * | 2020-06-23 | 2021-12-30 | Clininvent Research Pvt. Ltd. | A new cost effective and scalable process for synthesizing pure brivaracetam |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432030B (en) * | 2015-10-10 | 2019-06-25 | 苏州鹏旭医药科技有限公司 | A kind of preparation method of Bu Waxitan |
| CN108947883A (en) * | 2017-05-25 | 2018-12-07 | 北京万全德众医药生物技术有限公司 | The preparation of Bu Waxitan |
| CN109593055B (en) * | 2017-09-30 | 2022-04-26 | 上海医药工业研究院 | Preparation method of brivaracetam isomer (2S, 4S) |
| CN108947908B (en) * | 2018-07-11 | 2020-05-19 | 丽珠集团新北江制药股份有限公司 | New intermediate of brivaracetam with imidazole ring and synthesis method and application thereof |
| CN112110843A (en) * | 2019-06-20 | 2020-12-22 | 北京万全德众医药生物技术有限公司 | Novel preparation method of brivaracetam |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1740151A (en) * | 2000-02-23 | 2006-03-01 | Ucb公司 | 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses |
| KR20090017316A (en) * | 2007-08-14 | 2009-02-18 | 한국과학기술원 | ENANTIOSELECTIVE SYNTHESIS OF SUBSTITUTED gamma-BUTYROLACTONES |
| CN101528721A (en) * | 2006-11-06 | 2009-09-09 | 霍夫曼-拉罗奇有限公司 | Process for the preparation of (S)-4-fluoromethyl-dihydro-furan-2-one |
| CN101550099A (en) * | 2009-04-21 | 2009-10-07 | 无锡盛福药业有限公司 | Method for preparing Levetiracetam |
| CN101700996A (en) * | 2009-09-17 | 2010-05-05 | 扬州市天平化工厂有限公司 | Method for preparing gamma-tertiary butyl-chlorobenzene butanone |
| WO2010111622A2 (en) * | 2009-03-27 | 2010-09-30 | Codexis, Inc. | Amidases and methods of their use |
| US20140031368A1 (en) * | 2010-05-21 | 2014-01-30 | The Trustees Of Columbia University In The City Of New York | Selective hdac inhibitors |
| CN103819389A (en) * | 2014-02-17 | 2014-05-28 | 北京博泽德润医药科技开发有限公司 | Preparation method of levetiracetam |
| CN103910649A (en) * | 2014-04-29 | 2014-07-09 | 苏州天马精细化学品股份有限公司 | Synthetic method of (S)-N-[1-(aminocarbonyl)propyl]-4-chlorobutyrylamide serving as levetiracetam intermediate |
| US20140228579A1 (en) * | 2013-02-14 | 2014-08-14 | Brock Unviersity | Method for the catalytic reduction of acid chlorides and imidoyl chlorides |
-
2015
- 2015-07-21 CN CN201510430387.9A patent/CN106365986B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1740151A (en) * | 2000-02-23 | 2006-03-01 | Ucb公司 | 2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses |
| CN101528721A (en) * | 2006-11-06 | 2009-09-09 | 霍夫曼-拉罗奇有限公司 | Process for the preparation of (S)-4-fluoromethyl-dihydro-furan-2-one |
| KR20090017316A (en) * | 2007-08-14 | 2009-02-18 | 한국과학기술원 | ENANTIOSELECTIVE SYNTHESIS OF SUBSTITUTED gamma-BUTYROLACTONES |
| WO2010111622A2 (en) * | 2009-03-27 | 2010-09-30 | Codexis, Inc. | Amidases and methods of their use |
| CN101550099A (en) * | 2009-04-21 | 2009-10-07 | 无锡盛福药业有限公司 | Method for preparing Levetiracetam |
| CN101700996A (en) * | 2009-09-17 | 2010-05-05 | 扬州市天平化工厂有限公司 | Method for preparing gamma-tertiary butyl-chlorobenzene butanone |
| US20140031368A1 (en) * | 2010-05-21 | 2014-01-30 | The Trustees Of Columbia University In The City Of New York | Selective hdac inhibitors |
| US20140228579A1 (en) * | 2013-02-14 | 2014-08-14 | Brock Unviersity | Method for the catalytic reduction of acid chlorides and imidoyl chlorides |
| CN103819389A (en) * | 2014-02-17 | 2014-05-28 | 北京博泽德润医药科技开发有限公司 | Preparation method of levetiracetam |
| CN103910649A (en) * | 2014-04-29 | 2014-07-09 | 苏州天马精细化学品股份有限公司 | Synthetic method of (S)-N-[1-(aminocarbonyl)propyl]-4-chlorobutyrylamide serving as levetiracetam intermediate |
Non-Patent Citations (3)
| Title |
|---|
| Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity;Benoit M. Kenda等;《J. Med. Chem.》;20031225;第47卷(第3期);第530-549页 |
| Discovery of 4-Substituted Pyrrolidone Butanamides as New Agents with Significant Antiepileptic Activity;Benoit M. Kenda等;《J.Org.Chem.》;20031225;第47卷(第3期);第530-549页 |
| Enantiomerically Pure Synthesis of β-Substitutedγ-Butyrolactones: A Key Intermediate to ConciseSynthesis of Pregabalin;Taedong Ok et al.;《J.Org.Chem.》;20070823;第72卷;第7390-7393页 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021260721A1 (en) * | 2020-06-23 | 2021-12-30 | Clininvent Research Pvt. Ltd. | A new cost effective and scalable process for synthesizing pure brivaracetam |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106365986A (en) | 2017-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
| CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
| CN102617547B (en) | A kind of method preparing racemic nicotine | |
| CN106432030B (en) | A kind of preparation method of Bu Waxitan | |
| CN104478877B (en) | The method preparing Lei Dipawei intermediate | |
| CN101654419A (en) | Preparation method of fluvoxamine maleate | |
| CN105646285B (en) | One kind dimension Lactel sieve intermediate and its preparation method and application | |
| CN103402973B (en) | Compound and production method thereof, and for the production of the method for Ro 64-0796/002 | |
| CN110937985B (en) | Synthesis method of paradol | |
| CN104130146B (en) | (4S) preparation method of-3,6,9-tri-azepine-3,6,9-tri-(carboxymethyl)-4-(4-ethoxy benzyl) undecane diacids | |
| CN103787968B (en) | The preparation method of compound | |
| CN103497138B (en) | A kind ofly utilize zinc chloride, method that POTASSIUM BOROHYDRIDE prepares cis-hexahydroisoindoline | |
| CN103880756B (en) | The preparation method of a kind of Azilsartan intermediate | |
| CN109879806A (en) | A kind of isoquinolin indenes ether derivant and preparation method thereof | |
| CN104710346A (en) | Method for synthesizing cis-1-benzyl-3-methylamino-4-methyl-piperidine | |
| CN102627571B (en) | Preparation and synthesis method for chiral ammonium salt | |
| CN107641080A (en) | A kind of dihydronaphthalene ketones derivant containing spirane structure and preparation method thereof | |
| CN109265385B (en) | Synthesis process of chiral catalyst | |
| CN112250567A (en) | Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol | |
| CN102093257B (en) | Method for preparing 2,2-diisopropylpropionitrile | |
| CN113264850A (en) | Synthetic method of nootropic ketonic A | |
| CN103848756B (en) | Preparation method of teriflunomide and intermediate thereof | |
| CN110683943B (en) | Fluoro 1, 3-eneyne compound and preparation method thereof | |
| CN109096098A (en) | A kind of anti-form-1, the preparation method of 3- dihydroxy cyclobutane -1- carboxylic acid | |
| CN104610067A (en) | Synthetic method for rimantadine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20170201 Assignee: CHENGDA PHARMACEUTICALS Co.,Ltd. Assignor: SUZHOU PENGXU PHARMATECH Co.,Ltd. Contract record no.: X2021980001583 Denomination of invention: Compound, its preparation method and application in the synthesis of buwasitan Granted publication date: 20190108 License type: Common License Record date: 20210311 |
|
| EE01 | Entry into force of recordation of patent licensing contract |